ABSTRACT: The proposed study is a competitive renewal of our currently funded project that is investigating how epidemiological factors, clinical and pathological characteristics, and tumor marker expression influence the risk of second primary invasive contralateral breast cancer among survivors of a first primary invasive breast cancer. Here we propose to expand this work by evaluating factors that are related to risk of second primary breast cancers among ductal carcinoma in situ (DCIS) survivors. Incidence rates of DCIS have increased 7.2- fold from 1980 to 2001 in the United States, largely as a result of widespread breast cancer screening. DCIS lesions are very responsive to available therapies, and five-year disease-specific survival rates are close to 100%. However, DCIS survivors have a 3.4 to 8.6-fold higher risk of developing a second breast cancer compared to the risk that women in the general population have of developing a first breast cancer. The recent rapid rise in DCIS incidence rates has translated into a large and growing population of DCIS survivors who are particularly susceptible to developing a second breast cancer. Not all DCIS patients will go on to develop a second breast cancer, so certain surgical and adjuvant therapy combinations for DCIS constitute over- treatment for those at low risk of a second breast cancer, while others constitute under-treatment for those at high risk. At present, however, there is a lack of meaningful prognosticators to indicate which DCIS survivors are at high or low risk of developing a second breast cancer. Such prognosticators could be important guides to help these patients and their clinicians choose the most appropriate course of therapy and subsequent follow-up care. We propose to investigate how epidemiological, clinical, and histopathological characteristics of DCIS impact the risk of second primary breast cancers among DCIS survivors. We will recruit 515 patients diagnosed with DCIS and a verified subsequent second primary in situ or invasive breast cancer, and a control group consisting of 1,030 patients diagnosed only with DCIS to address the following specific aims: 1) How do epidemiological risk factors for breast cancer, including reproductive characteristics, anthropometric measures, use of exogenous hormones, mammographic density, and family history of breast cancer, influence the risks of second primary breast cancer overall, contralateral second primary breast cancer, and ipsilateral second primary breast cancer among DCIS survivors?; and 2) How do the clinical and histopathological features of DCIS, including treatments, tumor grade, and histological subtype impact risks of second primary breast cancer overall, contralateral second primary breast cancer, and ipsilateral second primary breast cancer among DCIS survivors? The proposed study will provide important information to the rapidly growing population of DCIS survivors as its results may help modulate their risk of developing a second primary breast cancer and inform their decision-making regarding DCIS treatments and subsequent breast cancer screening.